TY - JOUR TI - STAT3-mediated allelic imbalance of novel genetic variant Rs1047643 and B-cell-specific super-enhancer in association with systemic lupus erythematosus AU - Zhang, Yanfeng AU - Day, Kenneth AU - Absher, Devin M A2 - Guo, Xingyi A2 - Diamond, Betty VL - 11 PY - 2022 DA - 2022/02/21 SP - e72837 C1 - eLife 2022;11:e72837 DO - 10.7554/eLife.72837 UR - https://doi.org/10.7554/eLife.72837 AB - Mapping of allelic imbalance (AI) at heterozygous loci has the potential to establish links between genetic risk for disease and biological function. Leveraging multi-omics data for AI analysis and functional annotation, we discovered a novel functional risk variant rs1047643 at 8p23 in association with systemic lupus erythematosus (SLE). This variant displays dynamic AI of chromatin accessibility and allelic expression on FDFT1 gene in B cells with SLE. We further found a B-cell restricted super-enhancer (SE) that physically contacts with this SNP-residing locus, an interaction that also appears specifically in B cells. Quantitative analysis of chromatin accessibility and DNA methylation profiles further demonstrated that the SE exhibits aberrant activity in B cell development with SLE. Functional studies identified that STAT3, a master factor associated with autoimmune diseases, directly regulates both the AI of risk variant and the activity of SE in cultured B cells. Our study reveals that STAT3-mediated SE activity and cis-regulatory effects of SNP rs1047643 at 8p23 locus are associated with B cell deregulation in SLE. KW - allelic imbalance KW - super-enhancer KW - STAT3 KW - systemic lupus erythematosus KW - b-lymphocyte KW - chromatin accessibility JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -